Summary What we eat greatly impacts how our physiology and affects our propensity to get diseases such as obesity and diabetes. The bacteria that inhabit our intestine, our gut microbiota, greatly influence numerous physiological traits, including our nutritional intake, and also affect our response to therapeutic drugs. A major goal of biomedical research is to uncover the interplay between dietary nutrients and metabolites plus resident microbiota and the subsequent affect on our physiology. In addition, a major challenge is to dissect the mechanisms by which bacteria modulate the response to therapeutic drugs. We have developed an innovative interspecies systems biology model of the nematode C. elegans and its bacterial diet to address these questions. We have used this model to uncover bacterially derived micronutrients and metabolites that affect gene expression, development and fertility in the worm, and to identify a C. elegans metabolic regulatory network that mediates the response to bacterial nutrients. In addition, we have discovered mechanisms by which bacteria modulate the C. elegans response to several chemotherapeutic drugs. In the next project we use our demonstrated strength to investigate the effects of bacteria both broadly, in systems-level surveys and screens, and deeply with targeted mechanistic experiments. We will connect bacterial metabolism to host physiology and gene expression as well as the response to a variety of therapeutic drugs. The data obtained will provide an important stepping stone toward understanding how the microbiota can modulate human physiology in terms of nutrition and the response to xenobiotic compounds such as therapeutic drugs. This work, therefore, has long-term implications for nutrition, toxicology, as well as personalized and precision medicine.